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Cell Death & Disease May 2021Atherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture...
Atherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture of atherosclerotic plaque, and endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis. Intermedin (IMD) is a regulator of ERS. Here, we investigated whether IMD enhances atherosclerotic plaque stability by inhibiting ERS-CHOP-mediated apoptosis and subsequent inflammasome in macrophages. We studied the effects of IMD on features of plaque vulnerability in hyperlipemia apolipoprotein E-deficient (ApoE) mice. Six-week IMD infusion significantly reduced atherosclerotic lesion size. Of note, IMD lowered lesion macrophage content and necrotic core size and increased fibrous cap thickness and vascular smooth muscle cells (VSMCs) content thus reducing overall plaque vulnerability. Immunohistochemical analysis indicated that IMD administration prevented ERS activation in aortic lesions of ApoE mice, which was further confirmed in oxidized low-density lipoproteins (ox-LDL) induced macrophages. Similar to IMD, taurine (Tau), a non-selective ERS inhibitor significantly reduced atherosclerotic lesion size and plaque vulnerability. Moreover, C/EBP-homologous protein (CHOP), a pro-apoptosis transcription factor involved in ERS, was significantly increased in advanced lesion macrophages, and deficiency of CHOP stabilized atherosclerotic plaques in AopE mice. IMD decreased CHOP level and apoptosis in vivo and in macrophages treated with ox-LDL. In addition, IMD infusion ameliorated NLRP3 inflammasome and subsequent proinflammatory cytokines in vivo and in vitro. IMD may attenuate the progression of atherosclerotic lesions and plaque vulnerability by inhibiting ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation. The inhibitory effect of IMD on ERS-induced macrophages apoptosis was probably mediated by blocking CHOP activation.
Topics: Animals; Apoptosis; Humans; Inflammasomes; Macrophages; Mice; Neuropeptides; Peptide Fragments; Plaque, Atherosclerotic
PubMed: 33934111
DOI: 10.1038/s41419-021-03712-w -
European Journal of Pharmacology Dec 2017Macrophages are key players in atherosclerotic lesions, regulating the local inflammatory milieu and plaque stability by the secretion of many inflammatory molecules,... (Review)
Review
Macrophages are key players in atherosclerotic lesions, regulating the local inflammatory milieu and plaque stability by the secretion of many inflammatory molecules, growth factors and cytokines. Monocytes have long been considered to be the main source of plaque macrophages. However, recent findings provide evidence for proliferation of local macrophages or transdifferentiation from other vascular cells as alternative sources. Recent years of research focused on the further identification and characterisation of macrophage phenotypes and functions. In this review we describe the advances in our understanding of monocyte and macrophage heterogeneity and its implications for specific therapeutic interventions, aiming to reduce the ever growing significant risk of cardiovascular events without any detrimental side effects on the patient's immune response.
Topics: Animals; Humans; Macrophages; Molecular Targeted Therapy; Monocytes; Phenotype; Plaque, Atherosclerotic
PubMed: 28989084
DOI: 10.1016/j.ejphar.2017.10.005 -
Vascular Health and Risk Management 2015Identifying the mechanisms that convert a healthy vascular wall to an atherosclerotic wall is of major importance since the consequences may lead to a shortened... (Review)
Review
Identifying the mechanisms that convert a healthy vascular wall to an atherosclerotic wall is of major importance since the consequences may lead to a shortened lifespan. Classical risk factors (age, smoking, obesity, diabetes mellitus, hypertension, and dyslipidemia) may result in the progression of atherosclerotic lesions by processes including inflammation and lipid accumulation. Thus, the evaluation of blood lipids and the full lipid complement produced by cells, organisms, or tissues (lipidomics) is an issue of importance. In this review, we shall describe the recent progress in vascular health research using lipidomic advances. We will begin with an overview of vascular wall biology and lipids, followed by a short analysis of lipidomics. Finally, we shall focus on the clinical implications of lipidomics and studies that have examined lipidomic approaches and vascular health.
Topics: Atherosclerosis; Biomarkers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Metabolism; Lipids; Lipoproteins; Plaque, Atherosclerotic; Risk Factors
PubMed: 26109865
DOI: 10.2147/VHRM.S54874 -
International Journal of Molecular... May 2015A thrombotic occlusion of the vessel fed by ruptured coronary atherosclerotic plaque may result in unstable angina, myocardial infarction or death, whereas embolization... (Review)
Review
A thrombotic occlusion of the vessel fed by ruptured coronary atherosclerotic plaque may result in unstable angina, myocardial infarction or death, whereas embolization from a plaque in carotid arteries may result in transient ischemic attack or stroke. The atherosclerotic plaque prone to such clinical events is termed high-risk or vulnerable plaque, and its identification in humans before it becomes symptomatic has been elusive to date. Ultrasonic tissue characterization of the atherosclerotic plaque is possible with different techniques--such as vascular, transesophageal, and intravascular ultrasound--on a variety of arterial segments, including carotid, aorta, and coronary districts. The image analysis can be based on visual, video-densitometric or radiofrequency methods and identifies three distinct textural patterns: hypo-echoic (corresponding to lipid- and hemorrhage-rich plaque), iso- or moderately hyper-echoic (fibrotic or fibro-fatty plaque), and markedly hyperechoic with shadowing (calcific plaque). Hypoechoic or dishomogeneous plaques, with spotty microcalcification and large plaque burden, with plaque neovascularization and surface irregularities by contrast-enhanced ultrasound, are more prone to clinical complications than hyperechoic, extensively calcified, homogeneous plaques with limited plaque burden, smooth luminal plaque surface and absence of neovascularization. Plaque ultrasound morphology is important, along with plaque geometry, in determining the atherosclerotic prognostic burden in the individual patient. New quantitative methods beyond backscatter (to include speed of sound, attenuation, strain, temperature, and high order statistics) are under development to evaluate vascular tissues. Although not yet ready for widespread clinical use, tissue characterization is listed by the American Society of Echocardiography roadmap to 2020 as one of the most promising fields of application in cardiovascular ultrasound imaging, offering unique opportunities for the early detection and treatment of atherosclerotic disease.
Topics: Animals; Echocardiography; Endosonography; Humans; Plaque, Atherosclerotic; Ultrasonography, Interventional
PubMed: 25950760
DOI: 10.3390/ijms160510121 -
ACS Nano Jul 2023Atherosclerosis is a complex disease that can lead to life-threatening events, such as myocardial infarction and ischemic stroke. Despite the severity of this disease,...
Atherosclerosis is a complex disease that can lead to life-threatening events, such as myocardial infarction and ischemic stroke. Despite the severity of this disease, diagnosing plaque vulnerability remains challenging due to the lack of effective diagnostic tools. Conventional diagnostic protocols lack specificity and fail to predict the type of atherosclerotic lesion and the risk of plaque rupture. To address this issue, technologies are emerging, such as noninvasive medical imaging of atherosclerotic plaque with customized nanotechnological solutions. Modulating the biological interactions and contrast of nanoparticles in various imaging techniques, including magnetic resonance imaging, is possible through the careful design of their physicochemical properties. However, few examples of comparative studies between nanoparticles targeting different hallmarks of atherosclerosis exist to provide information about the plaque development stage. Our work demonstrates that Gd (III)-doped amorphous calcium carbonate nanoparticles are an effective tool for these comparative studies due to their high magnetic resonance contrast and physicochemical properties. In an animal model of atherosclerosis, we compare the imaging performance of three types of nanoparticles: bare amorphous calcium carbonate and those functionalized with the ligands alendronate (for microcalcification targeting) and trimannose (for inflammation targeting). Our study provides useful insights into ligand-mediated targeted imaging of atherosclerosis through a combination of imaging, tissue analysis, and targeting experiments.
Topics: Animals; Plaque, Atherosclerotic; Atherosclerosis; Magnetic Resonance Imaging; Nanoparticles
PubMed: 37399106
DOI: 10.1021/acsnano.3c03523 -
The Journal of Clinical Investigation Jul 2018Non-resolving inflammation drives the development of clinically dangerous atherosclerotic lesions by promoting sustained plaque inflammation, large necrotic cores, thin... (Review)
Review
Non-resolving inflammation drives the development of clinically dangerous atherosclerotic lesions by promoting sustained plaque inflammation, large necrotic cores, thin fibrous caps, and thrombosis. Resolution of inflammation is not merely a passive return to homeostasis, but rather an active process mediated by specific molecules, including fatty acid-derived specialized pro-resolving mediators (SPMs). In advanced atherosclerosis, there is an imbalance between levels of SPMs and proinflammatory lipid mediators, which results in sustained leukocyte influx into lesions, inflammatory macrophage polarization, and impaired efferocytosis. In animal models of advanced atherosclerosis, restoration of SPMs limits plaque progression by suppressing inflammation, enhancing efferocytosis, and promoting an increase in collagen cap thickness. This Review discusses the roles of non-resolving inflammation in atherosclerosis and highlights the unique therapeutic potential of SPMs in blocking the progression of clinically dangerous plaques.
Topics: Animals; Atherosclerosis; Disease Progression; Humans; Inflammation; Inflammation Mediators; Lipid Metabolism; Lipoxygenases; Models, Cardiovascular; Plaque, Atherosclerotic; Signal Transduction
PubMed: 30108191
DOI: 10.1172/JCI97950 -
Arteriosclerosis, Thrombosis, and... Apr 2019Atherosclerosis is the leading cause of cardiovascular morbidity and mortality. Over the past 2 decades, increasing research attention is converging on the early... (Review)
Review
Atherosclerosis is the leading cause of cardiovascular morbidity and mortality. Over the past 2 decades, increasing research attention is converging on the early detection and monitoring of atherosclerotic plaque. Among several invasive and noninvasive imaging modalities, magnetic resonance imaging (MRI) is emerging as a promising option. Advantages include its versatility, excellent soft tissue contrast for plaque characterization and lack of ionizing radiation. In this review, we will explore the recent advances in multicontrast and multiparametric imaging sequences that are bringing the aspiration of simultaneous arterial lumen, vessel wall, and plaque characterization closer to clinical feasibility. We also discuss the latest advances in molecular magnetic resonance and multimodal atherosclerosis imaging.
Topics: Carotid Arteries; Carotid Artery Diseases; Contrast Media; Coronary Angiography; Coronary Artery Disease; Forecasting; Gadolinium; Humans; Magnetic Resonance Angiography; Metal Nanoparticles; Multimodal Imaging; Plaque, Atherosclerotic; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography
PubMed: 30760017
DOI: 10.1161/ATVBAHA.118.311754 -
Journal of the American College of... Sep 2021The development of optical coherence tomography (OCT) has revolutionized our understanding of coronary artery disease. In vivo OCT research has paralleled with advances... (Review)
Review
The development of optical coherence tomography (OCT) has revolutionized our understanding of coronary artery disease. In vivo OCT research has paralleled with advances in computational fluid dynamics, providing additional insights in the various hemodynamic factors influencing plaque growth and stability. Recent OCT studies introduced a new concept of plaque healing in relation to clinical presentation. In addition to known mechanisms of acute coronary syndromes such as plaque rupture and plaque erosion, a new classification of calcified plaque was recently reported. This review will focus on important new insights that OCT has provided in recent years into coronary plaque development, progression, and destabilization, with a focus on the role of local hemodynamics and endothelial shear stress, the layered plaque (signature of previous subclinical plaque destabilization and healing), and the calcified culprit plaque.
Topics: Acute Coronary Syndrome; Algorithms; Cardiac Imaging Techniques; Coronary Circulation; Disease Progression; Hemodynamics; Humans; Plaque, Atherosclerotic; Tomography, Optical Coherence
PubMed: 34531029
DOI: 10.1016/j.jacc.2021.07.032 -
Current Opinion in Lipidology Oct 2014Atherosclerotic plaque rupture and subsequent acute events, such as myocardial infarction and stroke, contribute to the majority of cardiovascular-related deaths.... (Review)
Review
PURPOSE OF REVIEW
Atherosclerotic plaque rupture and subsequent acute events, such as myocardial infarction and stroke, contribute to the majority of cardiovascular-related deaths. Calcification has emerged as a significant predictor of cardiovascular morbidity and mortality, challenging previously held notions that calcifications stabilize atherosclerotic plaques. In this review, we address this discrepancy through recent findings that not all calcifications are equivalent in determining plaque stability.
RECENT FINDINGS
The risk associated with calcification is inversely associated with calcification density. As opposed to large calcifications that potentially stabilize the plaque, biomechanical modeling indicates that small microcalcifications within the plaque fibrous cap can lead to sufficient stress accumulation to cause plaque rupture. Microcalcifications appear to derive from matrix vesicles enriched in calcium-binding proteins that are released by cells within the plaque. Clinical detection of microcalcifications has been hampered by the lack of imaging resolution required for in-vivo visualization; however, recent studies have demonstrated promising new techniques to predict the presence of microcalcifications.
SUMMARY
Microcalcifications play a major role in destabilizing atherosclerotic plaques. The identification of critical characteristics that lead to instability along with new imaging modalities to detect their presence in vivo may allow early identification and prevention of acute cardiovascular events.
Topics: Calcinosis; Humans; Myocardial Infarction; Plaque, Atherosclerotic; Stroke
PubMed: 25188916
DOI: 10.1097/MOL.0000000000000105 -
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi =... Dec 2020Atherosclerosis is a complex and multi-factorial pathophysiological process. Researches over the past decades have shown that the development of atherosclerotic...
Atherosclerosis is a complex and multi-factorial pathophysiological process. Researches over the past decades have shown that the development of atherosclerotic vulnerable plaque is closely related to its components, morphology, and stress status. Biomechanical models have been developed by combining with medical imaging, biological experiments, and mechanical analysis, to study and analyze the biomechanical factors related to plaque vulnerability. Numerical simulation could quantify the dynamic changes of the microenvironment within the plaque, providing a method to represent the distribution of cellular and acellular components within the plaque microenvironment and to explore the interaction of lipid deposition, inflammation, angiogenesis, and other processes. Studying the pathological mechanism of plaque development would improve our understanding of cardiovascular disease and assist non-invasive inspection and early diagnosis of vulnerable plaques. The biomechanical models and numerical methods may serve as a theoretical support for designing and optimizing treatment strategies for vulnerable atherosclerosis.
Topics: Atherosclerosis; Biomechanical Phenomena; Computer Simulation; Humans; Inflammation; Models, Cardiovascular; Plaque, Atherosclerotic
PubMed: 33369333
DOI: 10.7507/1001-5515.202008038